Carvedilol for the Prevention of Anthracycline/Anti-HER2 Therapy Associated Cardiotoxicity Among Women With HER2-Positive Breast Cancer Using Myocardial Strain Imaging for Early Risk Stratification

Sponsor
Memorial Sloan Kettering Cancer Center (Other)
Overall Status
Completed
CT.gov ID
NCT02177175
Collaborator
(none)
82
2
2
84
41
0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to find out the effects, good and/or bad, of a beta blocker (carvedilol) on heart function during treatment with anti-HER2 medication(s) including trastuzumab (Herceptin).

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

This phase II placebo-controlled study will evaluate the effect of carvedilol, compared to placebo, on anthracycline/anti-HER2 therapy induced left ventricular dysfunction in patients with HER2-positive breast cancer who are receiving adjuvant or neoadjuvant therapy. All patients will undergo routine cardiac surveillance with 2D echocardiograms per standard of care at multiple time points which will align as closely as possible to the following: pre-anthracycline (baseline), pre-anti-HER2 therapy, and 3, 6, 9, and 12 months (+/- 4 weeks) after initiation of anti-HER2 therapy. In the case that standard of care echocardiograms are not done at these time points, either due to a delay in anti-cancer therapy or due to the patient's medical condition, the principal investigator will determine if the standard of care echocardiogram may be used in lieu of one of the time points listed. Additional speckle tracking strain analysis will be performed on these echocardiograms, and blood specimens will be drawn at several time points for biomarker analysis.

After completion of anthracycline treatment and prior to initiation of anti-HER2 therapy, 32 patients with abnormal myocardial strain, defined as global longitudinal strain < 19% or % change from baseline by > 11%, will be randomized in a 1:1 ratio to carvedilol versus placebo. Carvedilol will be administered twice daily for approximately 1 year OR until the end of anti-HER2 therapy, if it is discontinued prior to 1 year. Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily.

Study Design

Study Type:
Interventional
Actual Enrollment :
82 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Prevention
Official Title:
Carvedilol for the Prevention of Anthracycline/Anti-HER2 Therapy Associated Cardiotoxicity Among Women With HER2-Positive Breast Cancer Using Myocardial Strain Imaging for Early Risk Stratification
Actual Study Start Date :
Jun 24, 2014
Actual Primary Completion Date :
Jun 24, 2021
Actual Study Completion Date :
Jun 24, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Carvedilol

Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily.

Drug: Carvedilol

Placebo Comparator: placebo

Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily.

Other: placebo

Outcome Measures

Primary Outcome Measures

  1. Maximum Change in LVEF at 3 Months [3 months]

    Value at 3 months minus value at baseline

  2. Maximum Change in LVEF at 6 Months [6 months]

    Value at 6 months minus value at baseline

  3. Maximum Change in LVEF at 9 Months [9 months]

    Value at 9 months minus value at baseline

  4. Maximum Change in LVEF at 12 Months [12 months]

    Value at 12 months minus value at baseline

Secondary Outcome Measures

  1. Incidence of Abnormal LVEF at 12 Months [12 months]

    The study is designed to detect an intergroup difference of absolute difference of 10 percentage points (simple difference) in the change in LVEF between the experimental and control group. Ten percent is the change in LVEF that is associated with differing degrees of left ventricular dysfunction, and long-term studies among non-cancer patients have shown that outcomes differ among groups of patients who have LVEF differing by 10%.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
Female
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • Female

  • Age ≥ 18 years

  • Non-metastatic histologically confirmed primary invasive breast carcinoma

  • Pathologically confirmed HER2-positive breast cancer

  • Scheduled to receive anthracycline chemotherapy followed by anti-HER2 therapy at MSKCC

  • Able and willing to provide informed consent

  • Willing and able to comply with the requirements of the protocol

  • Able to swallow capsules

For Aim 2, all patients must meet the following criteria:
  • Meet all inclusion criteria above

  • LVEF > 50%

  • Abnormal global longitudinal strain (<19%, or a % decrease of ≥ 11% from baseline) prior to initiation of planned anti-HER2 therapy

  • Heart rate ≥ 50 beats per minute

  • Sitting systolic blood pressure > 90 mmHg

Exclusion Criteria:
  • Patients are to be excluded from randomization for Aim 2 of this study if they meet any of the following criteria:

  • Current treatment with ACE-inhibitors or beta blockers

  • Allergies or inability to tolerate beta blockers previously due to bradycardia, hypotension, or AV block.

  • Known history of NCI CTCAE (Version 4.0) Grade ≥ 2 symptomatic CHF, myocardial infarction within 12 months prior to randomization, significant symptoms (Grade ≥ 3) relating to left ventricular dysfunction, significant (moderate or severe) valvular disease, or significant cardiac arrhythmia (Grade ≥ 3)

  • Pre-menopausal women without a negative serum or urine pregnancy test within 4 weeks of starting treatment

  • Enrollment in a therapeutic intervention trial in the Breast Medicine service

Contacts and Locations

Locations

Site City State Country Postal Code
1 Memorial Sloan Kettering West Harrison Harrison New York United States 10604
2 Memorial Sloan Kettering Cancer Center New York New York United States 10065

Sponsors and Collaborators

  • Memorial Sloan Kettering Cancer Center

Investigators

  • Principal Investigator: Anthony Yu, MD, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT02177175
Other Study ID Numbers:
  • 14-099
First Posted:
Jun 27, 2014
Last Update Posted:
Jul 12, 2022
Last Verified:
Jun 1, 2021
Keywords provided by Memorial Sloan Kettering Cancer Center
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail 11 participants were randomized to treatment. 71 participants were not randomized to treatment.
Arm/Group Title Carvedilol Placebo
Arm/Group Description Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. Carvedilol Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. placebo
Period Title: Overall Study
STARTED 5 6
COMPLETED 4 6
NOT COMPLETED 1 0

Baseline Characteristics

Arm/Group Title Carvedilol Placebo Total
Arm/Group Description Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. Carvedilol Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. placebo Total of all reporting groups
Overall Participants 5 6 11
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]
45.6
55.2
50.8
Sex: Female, Male (Count of Participants)
Female
5
100%
6
100%
11
100%
Male
0
0%
0
0%
0
0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
1
20%
0
0%
1
9.1%
Not Hispanic or Latino
4
80%
6
100%
10
90.9%
Unknown or Not Reported
0
0%
0
0%
0
0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
0
0%
Asian
0
0%
2
33.3%
2
18.2%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
Black or African American
1
20%
1
16.7%
2
18.2%
White
2
40%
3
50%
5
45.5%
More than one race
0
0%
0
0%
0
0%
Unknown or Not Reported
2
40%
0
0%
2
18.2%
Region of Enrollment (Count of Participants)
United States
5
100%
6
100%
11
100%

Outcome Measures

1. Primary Outcome
Title Maximum Change in LVEF at 3 Months
Description Value at 3 months minus value at baseline
Time Frame 3 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Carvedilol Placebo
Arm/Group Description Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. Carvedilol Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. placebo
Measure Participants 5 6
Median (Full Range) [change in percent ejection fraction]
1
-5
2. Primary Outcome
Title Maximum Change in LVEF at 6 Months
Description Value at 6 months minus value at baseline
Time Frame 6 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Carvedilol Placebo
Arm/Group Description Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. Carvedilol Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. placebo
Measure Participants 5 6
Median (Full Range) [change in percent ejection fraction]
-2
-5
3. Primary Outcome
Title Maximum Change in LVEF at 9 Months
Description Value at 9 months minus value at baseline
Time Frame 9 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Carvedilol Placebo
Arm/Group Description Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. Carvedilol Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. placebo
Measure Participants 5 6
Median (Full Range) [change in percent ejection fraction]
-3.5
-5.5
4. Primary Outcome
Title Maximum Change in LVEF at 12 Months
Description Value at 12 months minus value at baseline
Time Frame 12 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Carvedilol Placebo
Arm/Group Description Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. Carvedilol Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. placebo
Measure Participants 5 6
Median (Full Range) [change in percent ejection fraction]
-2.5
-2
5. Secondary Outcome
Title Incidence of Abnormal LVEF at 12 Months
Description The study is designed to detect an intergroup difference of absolute difference of 10 percentage points (simple difference) in the change in LVEF between the experimental and control group. Ten percent is the change in LVEF that is associated with differing degrees of left ventricular dysfunction, and long-term studies among non-cancer patients have shown that outcomes differ among groups of patients who have LVEF differing by 10%.
Time Frame 12 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Carvedilol Placebo
Arm/Group Description Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. Carvedilol Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. placebo
Measure Participants 5 6
Abnormal LVEF
2
40%
1
16.7%
Normal LVEF
3
60%
5
83.3%

Adverse Events

Time Frame 12 months
Adverse Event Reporting Description
Arm/Group Title Carvedilol Placebo
Arm/Group Description Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. Carvedilol Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. placebo
All Cause Mortality
Carvedilol Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/5 (0%) 0/6 (0%)
Serious Adverse Events
Carvedilol Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 1/5 (20%) 0/6 (0%)
Infections and infestations
Skin infection 1/5 (20%) 0/6 (0%)
Other (Not Including Serious) Adverse Events
Carvedilol Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 5/5 (100%) 6/6 (100%)
Blood and lymphatic system disorders
Anemia 5/5 (100%) 6/6 (100%)
Investigations
Alanine aminotransferase increased 3/5 (60%) 1/6 (16.7%)
Alkaline phosphatase increased 4/5 (80%) 0/6 (0%)
Aspartate aminotransferase increased 2/5 (40%) 2/6 (33.3%)
Blood bilirubin increased 1/5 (20%) 0/6 (0%)
Neutrophil count decreased 0/5 (0%) 2/6 (33.3%)
Lymphocyte count decreased 2/5 (40%) 2/6 (33.3%)
Platelet count decreased 2/5 (40%) 2/6 (33.3%)
White blood cell decreased 2/5 (40%) 3/6 (50%)
Metabolism and nutrition disorders
Hypernatremia 1/5 (20%) 0/6 (0%)
Hyperglycemia 3/5 (60%) 4/6 (66.7%)
Hypoalbuminemia 2/5 (40%) 2/6 (33.3%)
Hypoglycemia 1/5 (20%) 0/6 (0%)
Hypokalemia 0/5 (0%) 1/6 (16.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Dr. Anthony Yu, MD
Organization Memorial Sloan Kettering Cancer Center
Phone 212-639-7932
Email yua3@mskcc.org
Responsible Party:
Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT02177175
Other Study ID Numbers:
  • 14-099
First Posted:
Jun 27, 2014
Last Update Posted:
Jul 12, 2022
Last Verified:
Jun 1, 2021